Medical management of severe obstructive sleep apnoea in two cases during the coronavirus disease 2019 pandemic.

OBJECTIVE: Severe paediatric obstructive sleep apnoea in typically developing children with adenotonsillar hypertrophy is primarily managed surgically. Non-emergency ENT surgery was paused early in the coronavirus disease 2019 pandemic and children were offered medical management for obstructive sleep apnoea. METHODS: A service evaluation was performed to assess the impact of continuous positive airway pressure alongside medical management for severe obstructive sleep apnoea. RESULTS: Over 5 months during 2020, in a tertiary care setting, two children (one boy and one girl), aged 2.7 years and 4.1 years, were offered continuous positive airway pressure and medical treatments for severe obstructive sleep apnoea whilst surgery was paused during the coronavirus disease 2019 pandemic. Both children failed to establish continuous positive airway pressure therapy because of ongoing disturbed sleep on ventilation, and they proceeded to adenotonsillectomy. Sleep-Related Breathing Disorder scale scores improved following surgical intervention. CONCLUSION: Continuous positive airway pressure therapy is poorly tolerated in children with severe obstructive sleep apnoea secondary to adenotonsillar hypertrophy. Surgery remains the most appropriate treatment.

Effects of artificial gravity during bed rest on bone metabolism in humans.

We report results from a study designed to explore the utility of artificial gravity (AG) as a countermeasure to bone loss induced by microgravity simulation. After baseline testing, 15 male subjects underwent 21 days of 6 degrees head-down bed rest to simulate the deconditioning associated with spaceflight. Eight of the subjects underwent 1 h of centrifugation (AG; 1 G(z) at the heart, 2.5 G(z) at the feet) each day for 21 days, whereas seven of the subjects served as untreated controls (Con). Blood and urine were collected before, during, and after bed rest for bone marker determinations. Bone mineral density (BMD) and bone mineral content (BMC) were determined by dual-energy X-ray absorptiometry and peripheral quantitative computerized tomography before and after bed rest. Urinary excretion of bone resorption markers increased during bed rest, but the AG and Con groups did not differ significantly. The same was true for serum C-telopeptide. During bed rest, bone alkaline phosphatase (ALP) and total ALP tended to be lower in the AG group (P = 0.08, P = 0.09). Neither BMC nor BMD changed significantly from the pre-bed rest period in AG or Con groups, and the two groups were not significantly different. However, when AG and Con data were combined, there was a significant (P < 0.05) effect of time for whole body total BMC and total hip and trochanter BMD. These data failed to demonstrate efficacy of this AG prescription to prevent the changes in bone metabolism observed during 3 wk of bed rest.

A rare cause of recurrent iron deficiency anaemia.

Gastro intestinal Stromal Tumours (GISTs) are a rare neoplasm of the gastrointestinal tract. They often grow silently and present late when surgical cure is not possible. Chemo and radiotherapy have a very poor success rate. We present a case of successful surgical removal of a gastrointestinal stromal tumour in a patient who presented with GI bleeding and a recurrent microcytic anaemia.

Recovery of spaceflight-induced bone loss: bone mineral density after long-duration missions as fitted with an exponential function.

The loss of bone mineral in NASA astronauts during spaceflight has been investigated throughout the more than 40 years of space travel. Consequently, it is a medical requirement at NASA Johnson Space Center (JSC) that changes in bone mass be monitored in crew members by measuring bone mineral density (BMD), with dual-energy X-ray absorptiometry (DXA) before and after flight, of astronauts who serve on long-duration missions (4-6 months). We evaluated this repository of medical data to track whether there is recovery of bone mineral that was lost during spaceflight. Our analysis was supplemented by BMD data from cosmonauts (by convention, a space traveler formally employed by the Russia Aviation and Space Agency or by the previous Soviet Union) who had also flown on long-duration missions. Data from a total of 45 individual crew members - a small number of whom flew on more than one mission - were used in this analysis. Changes in BMD (between 56 different sets of pre- and postflight measurements) were plotted as a function of time (days after landing). Plotted BMD changes were fitted to an exponential mathematical function that estimated: (i) BMD change on landing day (day 0) and (ii) the number of days after landing when 50% of the lost bone would be recovered ("50% recovery time") in the lumbar spine, trochanter, pelvis, femoral neck and calcaneus. In sum, averaged losses of bone mineral after long-duration spaceflight ranged between 2% and 9% across all sites with our recovery model predicting a 50% restoration of bone loss for all sites to be within 9 months.

Skeletal responses to space flight and the bed rest analog: a review.

The potential for loss of bone mineral mass due to space flight was recognized by space scientists even before man's first venture into micro-gravity. Early life science studies in both the U.S. and Russian space programs attempted to measure the effects of reduced gravity on skeletal homeostasis, and these measurements have become more sophisticated with time. Bone-related measurements have typically included: bone mineral density measured by X-ray absorptiometry and more recently CT scanning; bonerelated hormones and other biochemical markers of bone turnover; and calcium excretion and balance. These measurements, conducted over the last 4 decades, have shed light on the nature of disuse bone loss and have provided preliminary information regarding bone recovery. Ground-based analog (bed rest) studies have provided information complementary to the space flight data and have allowed the testing of various countermeasures to bone loss. In spite of the wealth of knowledge obtained thus far, many questions remain regarding bone loss, bone recovery, and the factors affecting these skeletal processes. This paper will summarize the skeletal data obtained to date by the U.S. and Russian space programs and in ground-based disuse studies. In addition, related body composition data will be briefly discussed, as will possible countermeasures to space flight-induced bone loss.

Inhaled bronchodilators for cystic fibrosis.

BACKGROUND: Recurrent wheeze and breathlessness are common in people with cystic fibrosis, and bronchodilators are commonly prescribed. Despite their wide-scale and often long-term use, there is limited objective evidence about their efficacy in cystic fibrosis. OBJECTIVES: To evaluate the effectiveness of inhaled bronchodilators in children and adults with cystic fibrosis. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic databases searches, and handsearches of relevant journals and abstract books of conference proceedings. Latest search of the Group's Trials Register: August 2005 SELECTION CRITERIA: Randomised or quasi-randomised trials comparing inhaled bronchodilators to placebo or another inhaled bronchodilator in people with CF, diagnosed clinically and by sweat or genetic testing and at all stages and severity of lung disease. DATA COLLECTION AND ANALYSIS: The authors independently extracted data and assessed trial quality. If data were missing, the primary author was contacted where possible. The data were subgrouped into classes of bronchodilator and for each class into short-term effects (less than one week) and long-term effects (greater or equal to one week). MAIN RESULTS: The search identified 43 references. Fourteen trials, with a total of 257 participants, were suitable for inclusion. The trials were all cross-over in design; in this case a meta-analysis was not possible. There were varied conclusions from the different trials, reflecting their heterogeneity. Compared to placebo, short-acting beta-2 agonists increased forced expiratory volume at one second (FEV(1)) in the short term in three out of five trials, and in the long-term increased peak expiratory flow rate in individuals who had been shown to have bronchial hyperreactivity or bronchodilator responsiveness or both. Compared to placebo, long-acting beta-2 agonists increased FEV(1) and forced expiratory flow between 25% and 75% of expiratory flow (FEF 25-75%) in the short term in participants known to have bronchodilator responsiveness, but produced inconsistent results in long-term trials. Short acting-anticholinergics had no consistent effect on lung function tests in either the short or the long term. We found no published trials of fenoterol, formoterol or tiotropium and the use of these agents in cystic fibrosis cannot be supported. AUTHORS' CONCLUSIONS: It was not possible to determine fully the effectiveness of inhaled bronchodilators in cystic fibrosis as a meta-analysis was not possible. However, both short and long-acting beta-2 agonists can be beneficial both in the short and long term in individuals with demonstrable bronchodilator responsiveness or bronchial hyperrresponsiveness.

Resistance exercise as a countermeasure to disuse-induced bone loss.

During spaceflight, skeletal unloading results in loss of bone mineral density (BMD). This occurs primarily in the spine and lower body regions. This loss of skeletal mass could prove hazardous to astronauts on flights of long duration. In this study, intense resistance exercise was used to test whether a training regimen would prevent the loss of BMD that accompanies disuse. Nine subjects (5 men, 4 women) participated in a supine maximal resistance exercise training program during 17 wk of horizontal bed rest. These subjects were compared with 18 control subjects (13 men, 5 women) who followed the same bed rest protocol without exercise. Determination of treatment effect was based on measures of BMD, bone metabolism markers, and calcium balance obtained before, during, and after bed rest. Exercisers and controls had significantly (P < 0.05) different means, represented by the respective following percent changes: lumbar spine BMD, +3% vs. -1%; total hip BMD, +1% vs. -3%; calcaneus BMD, +1% vs. -9%; pelvis BMD, -0.5% vs. -3%; total body BMD, 0% vs. -1%; bone-specific alkaline phosphatase, +64% vs. 0%; alkaline phosphatase, +31% vs. +5%; osteocalcin, +43% vs. +10%; 1,25 dihydroxyvitamin D, +12% vs. -15%; parathyroid hormone intact molecule, +18% vs. -25%; and serum and ionized calcium, -1% vs. +1%. The difference in net calcium balance was also significant (+21 mg/day vs. -199 mg/day, exercise vs. control). The gastrocnemius and soleus muscle volumes decreased significantly in the exercise group, but the loss was significantly less than observed in the control group. The results indicate that resistance exercise had a positive treatment effect and thus might be useful as a countermeasure to prevent the deleterious skeletal changes associated with long-duration spaceflight.

The use of 17-hydroxyprogesterone in the diagnosis of canine hyperadrenocorticism.

A number of dogs are seen with clinical signs consistent with hyperadrenocorticism (HAC), supporting CBC and biochemical findings, but the disease cannot be confirmed with either the ACTH stimulation test or the low-dose dexamethasone suppression test (LDDST). Therefore, another screening test is required to aid diagnosis in these atypical cases of HAC. The aim of this study was to investigate whether measuring 17-hydroxyprogesterone (OHP) concentrations could be used in this role. Plasma cortisol and OHP concentrations were measured in dogs with clinical signs suggestive of HAC before and after administration of exogenous ACTH. In dogs with HAC, plasma OHP showed an exaggerated response to ACTH stimulation. This was seen in both typical cases of HAC with a positive cortisol response to ACTH administration and in atypical cases with negative screening test results. The test can be performed on plasma already taken for a conventional ACTH stimulation test. Post-ACTH OHP concentrations decreased after treatment with mitotane or adrenalectomy. These results suggest that OHP measurements can be used as an aid to diagnose and manage canine HAC.

Alendronate as an effective countermeasure to disuse induced bone loss.

Microgravity, similar to disuse immobilization on earth, causes rapid bone loss. This loss is believed to be an adaptive response to the reduced musculoskeletal forces in space and occurs gradually enough that changes occurring during short duration space flight are not a concern. Bone loss, however, will be a major impediment for long duration missions if effective countermeasures are not developed and implemented. Bed rest is used to simulate the reduced mechanical forces in humans and was used to test the hypothesis that oral alendronate would reduce the effects of long duration (17 weeks) inactivity on bone. Eight male subjects were given daily oral doses of alendronate during 17 weeks of horizontal bed rest and compared with 13 male control subjects not given the drug. Efficacy was evaluated based on measurements of bone markers, calcium balance and bone density performed before, during and after the bed rest. The results show that oral alendronate attenuates most of the characteristic changes in bone that are associated with long duration bed rest and presumably space flight.

The management of urinary calculi in pregnancy.

When a pregnant patient presents with a urinary calculus, the customary investigations and management must change in order to take into account the well-being of the developing fetus. Transabdominal or endovaginal ultrasound should be the initial imaging modality used in order to establish the diagnosis. A plain abdominal X-ray, limited intravenous pyelography, or retrograde pyelography is used secondarily if a definitive diagnosis is lacking. The treatment of first choice for urolithiasis in pregnancy is conservative, because 70-80% of stones will pass spontaneously. If conservative management fails, or in cases of sepsis, obstruction of a solitary kidney, or bilateral ureteric obstruction, then surgical intervention is indicated. Traditional surgical management consists of draining the obstructed collecting system with a ureteral stent or percutaneous nephrostomy tube with definitive treatment of the stone in the post-partum period. Ureteroscopic lithotripsy and stone extraction is another option that has been used safely and reliably with increasing frequency in many centers. Despite recent reports of using extracorporeal shock-wave lithotripsy, this treatment is still considered contraindicated in pregnancy.

Cortisol response to two different doses of intravenous synthetic ACTH (tetracosactrin) in overweight cats.

Fifteen middle-aged to older, overweight cats attending a first-opinion clinic were investigated to rule out hyperadrenocorticism as a cause of their weight problem, using two different protocols for the adrenocorticotropic hormone (ACTH) stimulation test. The cats received intravenous synthetic ACTH (tetracosactrin) at an initial dose of 125 microg; a second test was performed between two and three weeks later, using a dose of 250 microg intravenously. The mean basal serum cortisol concentration was 203 nmol/litre (range 81 to 354 nmol/litre). The highest mean serum cortisol concentration occurred at 60 minutes following the 125 microg dose and at 120 minutes following the 250 microg dose. There was, however, no statistically significant difference between these peak cortisol concentrations attained using either dose of tetracosactrin. A significantly higher mean serum cortisol concentration was attained after the higher dose at the 180 minutes time point, indicating a more prolonged response when compared with the lower dose. The cats were followed up for one year after the initial investigations and none were found to develop hyperadrenocorticism during this time.

Targeting of venom phospholipases: the strongly anticoagulant phospholipase A(2) from Naja nigricollis venom binds to coagulation factor Xa to inhibit the prothrombinase complex.

The strongly anticoagulant basic phospholipase A(2) (CM-IV) from Naja nigricollis venom has previously been shown to inhibit the prothrombinase complex of the coagulation cascade by a novel nonenzymatic mechanism (S. Stefansson, R. M. Kini, and H. J. Evans Biochemistry 29, 7742-7746, 1990). That work indicated that CM-IV is a noncompetitive inhibitor and thus it interacts with either factor Va or factor Xa, or both. We further examined the interaction of CM-IV and the protein components of the prothrombinase complex. Isothermal calorimetry studies indicate that CM-IV does not bind to prothrombin or factor Va, but only to factor Xa. CM-IV has no effect on the cleavage of prothrombin by factor Xa in the absence of factor Va. However, in the presence of factor Va, CM-IV inhibits thrombin formation by factor Xa. With a constant amount of CM-IV, raising the concentration of factor Va relieved the inhibition. The phospholipase A(2) enzyme inhibits by competing with factor Va for binding to factor Xa and thus prevents formation of the normal Xa-Va complex or replaces bound factor Va from the complex. Thus factor Xa is the target protein of this anticoagulant phospholipase A(2), which exerts its anticoagulant effect by protein-protein rather than protein-phospholipid interactions.

Flanking proline residues identify the L-type Ca2+ channel binding site of calciseptine and FS2.

Calciseptine and FS2 are 60-amino acid polypeptides, isolated from venom of the black mamba (Dendroaspis polylepis polylepis), that block voltage-dependent L-type Ca2+ channels. We predicted that these polypeptides contain an identical functional site between residues 43 and 46 by searching for proline residues that mark the flanks of protein-protein interaction sites [Kini, R. M., and Evans, H. J. (1966) FEBS Lett. 385, 81-86]. The predicted Ca2+ channel binding site also occurs in closely related toxins, C10S2C2 and S4C8. Therefore, it is likely that these toxins also will block L-type Ca2+ channels. To test the proposed binding site on calciseptine and FS2, an eight-residue peptide, named L-calchin (L-type calcium channel inhibitor), was synthesized and examined for biological activity. As expected for an L-type Ca2+ channel blocker, L-calchin reduced peak systolic and developed pressure in isolated rat heart Langendorff preparations without affecting diastolic pressure or heart rate. Furthermore, L-calchin caused a voltage-independent block of L-type Ca2+ channel currents in whole-cell patch-clamped rabbit ventricular myocytes. Thus the synthetic peptide exhibits the L-type Ca2+ channel blocking properties of the parent molecules, calciseptine and FS2, but with a lower potency. These results strongly support the identification of a site in calciseptine and FS2 that is important for binding to L-type Ca2+ channels and reinforce the importance of proline brackets flanking protein-protein interaction sites.

Prediction of potential protein-protein interaction sites from amino acid sequence. Identification of a fibrin polymerization site.

Identification of a protein-protein interaction site is an important step that has significant potential to clarify structure-function relationships of proteins and drug design. We propose here a unique predictive method to identify protein-protein interaction sites based on the observation that proline is the most common residue found in the flanking segments of interaction sites [Kini, R.M. and Evans, H.J. (1995) Biochem. Biophys. Res. Commun. 212, 1115-1124]. Accordingly, the interaction sites of proteins might be predicted directly from the amino acid sequence based on the presence of proline brackets. Using this strategy, we have predicted a polymerization site in the epitope of the Aalpha-chain of fibrinogen recognized by a monoclonal antibody, 9E9 which inhibits fibrin polymerization [Cierniewski, C.S. and Budzynski, A.Z. (1992) Biochemistry 31, 4248-4253]. The synthetic peptide comprising this predicted site inhibited the coagulation of human blood and allosterically interfered in fibrin polymerization. This is the first known allosteric polymerization site of fibrinogen. Thus the results validate the predicted site and the method for prediction. This unique predictive method should help in identifying the interaction sites of many proteins.

The role of enzymatic activity in inhibition of the extrinsic tenase complex by phospholipase A2 isoenzymes from Naja nigricollis venom.

Three phospholipase A2 isoenzymes from Naja nigricollis venom inhibit the extrinsic tenase complex. We examined the role of their enzymatic activity in this inhibition by studying the effects of native and His-modified enzymes. Only CM-IV of the His-modified, catalytically inactive proteins showed significant inhibition of the activity of the complex. This indicates that strongly anticoagulant CM-IV inhibits the complex by both enzymatic and nonenzymatic mechanisms, whereas the weakly anticoagulant isoenzymes, CM-I and CM-II, inhibit primarily by catalytic degradation of phospholipids. This indicates a functional difference in the mode of inhibition between strongly and weakly anticoagulant phospholipase A2 enzymes.

A novel approach to the design of potent bioactive peptides by incorporation of proline brackets: antiplatelet effects of Arg-Gly-Asp peptides.

Enhancing the potency of peptides is a critical and important step in the development of peptide drugs. We have proposed that proline residues flanking protein-protein interaction sites perform a structural role in enhancing their interaction [R.M. Kini and H.J. Evans, Biochem. Biophys. Res. Commun. 212 (1995) 1115-1124]. To test this theory, we incorporated proline residues on either or both sides of the interaction site of an antiplatelet peptide, IARGDMNA and determined the inhibitory potency of the peptides in whole blood aggregation. Inclusion of one proline residue, on either the amino or carboxy terminal side of the interaction site, enhances the antiplatelet activity to approximately the same extent (1.5- to 2.5-fold). Incorporation of proline residues on both sides enhances the activity by 7- to 13-fold. This enhancement of the biological activity of the peptide is probably due to a reduction in the number of possible conformations of the peptide, without introducing the rigidity that would accompany cyclization. Incorporation of proline brackets thus provides a novel approach to the design and development of more potent peptide drugs and ligands.